Progesterone is a naturally occurring steroid which is the main steroid secreted by women during their reproductive years. This steroid has been studied extensively and has been found to be a major precursor in the biosynthesis of most other steroids, particularly glucocorticoids, androgens and estrogens. Progesterone also stimulates the growth of the uterus and a number of specific changes in the endometrium and myometrium. It is essential for the development of decidual tissue and the differentiation of luminal and glandular epithelial tissue. Progesterone also plays several roles in gestation, including breast enlargement, inhibition of uterine contractility, maintenance of gestation, immunological protection of the embryo, and inhibition of prostaglandin synthesis.
Progestins include the natural progestin, progesterone, as well as the synthetic progestins, such as medroxyprogesterone acetate (MPA). Progestins have been used pharmaceutically in the treatment of a number of clinical disorders such as luteal phase deficiency, dysfunctional uterine bleeding, endometriosis, endometrial carcinoma, benign breast disease, pre-eclampsia, and assisting in vitro fertilization, preventing early abortion and reducing the occurrence of endometrial hyperplasia in estrogen replacement therapy (ERT).
The most common progestational agents used are the synthetic progestins, which are accompanied by undesirable side effects such as depression and water retention. Additionally, many of the synthetic progestins derived from 19-nor-testosterone reverse the positive effects of estrogen on lipoprotein (HDL) levels. In contrast, natural progesterone does not cause water retention, is rarely associated with depression and has no adverse effects upon lipid levels.
There have been many difficulties in administering natural progesterone at the appropriate serum and tissue levels to patients. When given orally, progesterone is rapidly metabolized. See e.g., Adlecruz, H. and Martin, F. J. Steroid Biochem., 13:231-244 (1980) and Maxson, W. S., and Hargrove, J. T., Fertil. Steril., 44:622-626 (1985).
Rectal administration of progestins has also been attempted with 25 mg and 100 mg doses of natural progesterone, which achieved peak plasma levels at 4 to 8 hours after administration followed by a gradual decline, but the maintenance of a stable plasma level has been difficult with this route. Maxson, W. S. Clinical Obstet. Gynecol., 30: 465-477 (1987); Nillius, S. J. and Johansson, E. D. B. Am. J. Obstet. Gynecol., 110: 470-479 (1971). Sublingual administration resulted in rapid appearance of progesterone in the serum reaching peaklvalues of up to 10 times basal levels, but returning to basal levels within twenty-four hours. Villanueva, B., et aL, Fertil. Steril., 35: 433-437 (1981). Nasal administration, using 20 mg and 30 mg doses, achieved mean maximum concentrations of 2.1 and 4.1 ng/ml, respectively, at approximately 30 and 240 minutes, respectively.
Intramuscular administration of progesterone has been attempted with 100 mg doses which achieved 40 to 50 ng/ml serum concentrations in two to eight hours. Nillius, S. J. and Johansson, E. D. B., Am. J. Obstet. Gynecol., 110: 470-479 (1971). Such administration has shown that such injections need to be given every day or on alternate days to produce results. cf.id.at 476. Subdermal administration has also been assayed, with six 100 mg progesterone pellets being implanted in postpartum women. Croxatto, H. B., et al., Acta Endocrinol, 100: 630 (1982). Progesterone levels reached a peak of 4.4 ng/ml within the first week after insertion and reached a mean peak level of 1.9 ng/ml six months after implantation. Progestin implants are not practical in cyclical therapy and moreover, physiological levels of progestin are not achieved. ("Cyclical" therapy means that the progestin is administered off and on, typically for a portion of each 28-day cycle or each calendar month. For example, cyclical administration could be daily, or every other day, only on days 15 through 20 of each 28-day cycle, or only for the first five days each month. "Constant" or "continuous" therapy means that the drug is administered regularly, whether it is daily, every other day, weekly, or otherwise, without regard, for example, to the 28-day cycle or the calendar month.)
It has been demonstrated that topically applied radioactive progesterone can be absorbed through the skin. Mauvais-Jarvis, Progesterone., et al., J. Clin. Endocrinol. Metab., 29: 1580-1587 (1969). Labeled metabolites were recovered in the urine at 48 hours after topical administration. However, the absorption was only 10% of the applied dose. The high fat solubility of progesterone is responsible for the prolonged retention of this steroid and the extensive local metabolism reduces the systemic effect of the steroid. It has been shown that treatment with topical application of progesterone to the breast produces no significant endometrial effects. Sitruk-Ware, R., et al., J. Clin. Endocrin. Metab., 44: 771-774 (1977).
Progestins have also been administered vaginally to postmenopausal women receiving ERT. 50 mg/mil of progesterone in a suspension containing carboxymethyl cellulose and methyl cellulose which was inserted into the vagina was characterized by a rapid absorption of the progesterone across the vaginal mucosa. There was an immediate appearance of the hormone in the peripheral circulation resulting in a 10-fold increase over the baseline serum levels (0.34 ng/ml) after 15 minutes. The peak levels were obtained 1 or 2 hours after administration and represented a thirty- to forty-fold increase over baseline levels (12.25 ng/ml). The serum levels remained at this level over the next seven hours, declining over the next ten hours to 3.68 ng/ml. Villanueva, B., et al., Fertil. Steril., 35: 433-437 (1981). These results suggested that the absorption of progestins was enhanced in women also undergoing ERT.
As described in U.S. Pat. No. 5,543,150 ("the '150 Patent"), which is incorporated herein by reference, it now appears that the bioadhesive formulation used with the instant invention can provide local vaginal administration of progestins to yield significant local drug levels while maintaining serum levels low enough to avoid most of the undesired side effects. See also, Warren, M. P., et al., Evaluation of Crinone.RTM., a Transvaginally Administered Progesterone Containing Bioadhesive Gel, in Women with Secondary Amenorrhea, Abstract, Presented at the 8th International Congress on the Menopause, Sydney, Australia, 1996. And as described in U.S. patent application Ser. No. 08/743,153, which is incorporated herein by reference, it also appears that progesterone can be administered for the purpose of treating or reducing ischemia or incidence of cardiovascular events.
Treatments of menopausal and post-menopausal women involving administration of progestins in cyclical association with estrogen induces the physiological sequence of endometrial changes normally encountered in the menstrual cycle. Such treatments usually administer progestins, usually daily, over a period of about 10 to 14 days each month. However, the withdrawal bleeding that results from such administration is typically irregular and unpredictable, and often begins as early as about the fourth day following the first progestin dose. See, Archer, D. F., et al., Bleeding Patterns in Post-menopausal Women Taking Continuous Combined or Sequential Regimens of Conjugated Estrogens with Medroxyprogesterone Acetate, Obstet. Gynecol., 83:686-92 (1994).